There is steadily increasing evidence that iron deprivation may be a useful tool in the development of new treatment strategies against cancer. As potential new therapies involving iron deprivation are developed from in vitro testing, a crucial next step is to try to develop some appreciation for both efficacy and potential toxicity by the use of appropriate animal models. The longterm objective of this research is to provide an animal model system for testing combination treatments that utilize anti-transferrin receptor monoclonal antibodies (anti-Tfr Mabs). The first specific aim is to evaluate the efficacy and toxicity of combination treatment with a pair of synergistic IgG rat anti-mouse anti- Tfr Mabs and an hydroxyethylstarch conjugate of deferoxamine (HES-DFO). The second specific aim is to screen new combinations of reagents (to include all-trans retinoic acid, non-steroidal anti-inflammatory drugs, wortmannin, and tyrphostins) with IgG anti-Tfr Mabs in vitro for activity against a panel of murine hematopoietic and non-hematopoietic tumors. Interesting combinations would then be taken to an in vivo setting to further define potential efficacy and toxicity. Using the 38C13 tumor model in C3H mice, dose response titrations of both IgG anti-Tfr Mabs and HES-DFO will be undertaken while the other agent is held at a constant concentration. Plasma levels and pharmacokinetics will be ascertained for both HES-DFO and IgG anti-Tfr Mabs by spectrophotometric and flow cytometric methods, respectively. Altered schedules of administration will also be tested with an emphasis on starting with DFO pre-treatment and narrowing the time of overlap of combination treatment. Hematologic toxicity will be assessed by an automated analyzer. Other patterns of tissue damage will be assessed by comprehensive post mortem studies. Combination treatment with IgG anti-Tfr Mabs and other reagents will be undertaken in vitro against the panel of tumors (including neuroblastomas, melanomas, and tumors of lung and gut origin) via two-way dose response curves. Growth inhibition will be assessed by both thymidine incorporation and MTT assays. Combinations that appear to be interesting in vitro will then be subjected to in vivo testing in a manner similar to described for HES-DFO and IgG anti-Tfr Mabs. Overall, these studies will assist in the evaluation of new treatment strategies for cancer - the second leading cause of death in the United States.